The proposed research is directed toward investigating KSHV immune evasion strategies, specifically focused with the roles of viral interferon regulatory factor (vIRF)-mediated deregulation of IFN response and growth control for KSHV persistence and pathogenesis. Our previous studies have demonstrated how KSHV comprehensively inhibits host IFN-mediated signal transduction and deregulates growth control: (1) vIRF1 downregulates cellular IRF3 and p53 transcriptional activity by interacting with p300 transcriptional coactivator and ATM kinase, respectively; (2) vIRF3 inhibits IRF7 by suppressing its DNA binding activity and induces angiogenesis by enhancing HIF11 stability; (3) vIRF4 downregulates IFN1 gene expression and upregulates translational control. Furthermore, we have shown how host elicits IFN signal transduction upon viral infection. Finally, we have successfully developed the non-human primate for KSHV persistent infection. We would stress that this is the first animal model that significantly recapitulates important aspects of KSHV infection in human and thus provides a unique opportunity to dissect the molecular mechanisms of KSHV infection and persistence directly in primate. To further unravel how KSHV establishes a life-long infection, we continuously investigate a novel viral strategy that KSHV vIRFs deregulate host innate immunity and cell growth control to establish persistent infection. Our biochemical and cell biology studies will define in greater detail the molecular mechanisms used by vIRFs to inhibit IFN-mediated innate immunity and host p53 tumor suppressor-mediated cell growth control. To correlate the effects of vIRFs on IFN response and cell growth regulation with viral life cycle in vivo, we will then test how the loss of vIRF gene(s) affects the KSHV persistent infection in primates. With well-established in vitro and in vivo experimental conditions, the proposed study will detail the roles of vIRFs, IFN antagonist and cell growth deregulator, in viral persistence. This proposal is highly innovative and the successful outcome should be a major discovery that significantly impacts the understanding of KSHV biology and may reveal targets for novel therapeutic strategies. PUBLIC HEALTH RELEVANCE Most viruses have evolved immune evasion strategies to protect themselves against host interferon (IFN) responses, elaborating viral proteins as a counter-defense against the host IFN defenses. During the last granting period, we have demonstrated a novel mechanism of KSHV to antagonize cellular IFN-mediated anti-viral activity by incorporating viral homologs to the cellular interferon regulatory factors (IRFs), and have also developed a primate model for KSHV persistent infection that significantly recapitulates important aspects of KSHV infection in human. To further unravel how KSHV establishes a life-long infection, we will continuously investigate a novel viral immune evasion strategy that KSHV vIRFs deregulate host IFN-mediated innate immunity and tumor suppressor-mediated cell growth control to establish persistent infection.